Rapid synthesis of azoindolizine derivatives via aryldiazonium salts

A practical, rapid, and efficient method for the synthesis of azoindolizine derivatives via aryldiazonium salts with excellent yields was reported. Firstly, the corresponding aniline derivatives were synthesized via a simple and rapid method. Then, the optimal reaction conditions were investigated using a variety of protic and aprotic solvents that demonstrating the robustness of the approach. Finally, the applicability of this method to various sources of indolizine and phenyldiazonium tetrafluoroborate salts was expanded.

bs. Melting points were determined on Gallenkamp melting point apparatus.Aryl diazonium salts (2a-g) were prepared according to literature [34,35].All NMR spectra were reported in the Supporting Information.

General procedure 2 (GP2): Preparation of azoindolizine derivatives (3a-h).
To a solution of indolizine (0.25 mmol) in CH 2 Cl 2 (3 mL), aryl diazonium tetrafluoroborate (0.25 mmol) was added and the mixture was stirred at room temperature for 5 min.After the reaction was complete the solvent was evaporated under reduced pressure.The residue was rinsed with diethyl ether to give the desired product.

Results
Initially, aryl diazonium salts were synthesized from the corresponding aniline derivatives with good yields.The study commenced by using indolizine and phenyldiazonium tetrafluoroborate salt as standard substrates to investigate the optimal reaction conditions (Table ).The impact of solvents on the reaction yield was assessed.Various protic solvents, including H 2 O, EtOH, and MeOH, were tested, resulting in the desired product 3a being obtained in yields ranging from 75% to 77% (Table, entries 1-3).When various aprotic solvents, including THF, CH 3 CN, DMF, DMSO, and CH 2 Cl 2 , were employed, product 3a was achieved with yields ranging from 80% to 95% (Table , entries 4-8).Notably, aprotic solvents were observed to be considerably more favorable than protic solvents, with CH 2 Cl 2 yielding the highest results.Following the completion of screenings, these optimized conditions were applied, which consisted of 0.25 mmol of indolizine (1), 0.25 mmol of phenyldiazonium tetrafluoroborate salt (2), room temperature (rt), a 5-min reaction time, and CH 2 Cl 2 as the solvent.This allowed us to broaden the applicability of this method to various sources of indolizine and phenyldiazonium tetrafluoroborate salt.

Discussion
In this context, a practical, rapid, and efficient method for the synthesis of azoindolizine derivatives via aryldiazonium salts was successfully developed.Through systematic optimization of reaction conditions, achieved excellent yields (up to 98%), demonstrating the robustness of the approach.Additionally, the scope of this method to various sources of indolizine and aryldiazonium tetrafluoroborate salt, enhancing its applicability was expanded.

Acknowledgment
This study was supported by the Scientific and Technical Research Council of Türkiye TÜBİTAK-BİDEB (project number: 118C579).

Supporting information
https://aperta.ulakbim.gov.tr/record/263864 Having successfully established the optimized reaction conditions, the subsequent step was to investigate the reaction's applicability to a range of diazonium tetrafluoroborate salts (Scheme 2).Initially, the reaction was assessed using various substituents on the phenyl ring of the diazonium tetrafluoroborate salt.For this purpose, indolizine (1) was treated with different diazonium tetrafluoroborate salts 2a-g.The reaction of indolizines (1) with p-halogenated diazonium tetrafluoroborate salts were transformed into the corresponding products 3b-3c with excellent yields of 95% and 97% respectively.Delightedly, substituted diazonium tetrafluoroborate salts with electron-donating groups, whether the substituents are at meta-, or para-position, afforded the corresponding products 3d-3g in high yields (94%-96%).Next, the applicability of indolizine was evaluated.As expected, the reaction of 2-(p-tolyl)indolizine with phenyldiazonium tetrafluoroborate salt was established as the desired product 3h in excellent yield (94%).

Scheme 1 .Scheme 1 .
Scheme 1.Some examples of pharmaceuticals featuring the indolizine motif.Scheme 1.Some examples of pharmaceuticals featuring the indolizine motif.

Table .
Solvent optimization study of the formation of 3a.